tbuckley/cabot-search huggingface dataset:
Surgical subtypes and survival in stage II osteosarcoma: A National Cancer Database (NCDB) analysis.
Authors: Vincent Eaton, Connor Tupper, Kevin McMahon, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2022)

e23513 Background: Osteosarcoma (OSC) is the most common primary malignancy of bone and is most commonly diagnosed in its earlier stages (I and II). Standard of care involves a combination of chemotherapy and surgical resection and, to date, there are few reports examining different surgical subtypes in these patients. This study aims to analyze different surgical subtypes in OSC patients to assess survival, particularly in stage II. Methods: Using the NCDB, patients diagnosed with stage II OSC between 2004-2018 were identified using ICD-O-3 histology codes 9180-9193. The cohort was analyzed to determine if they received any of the following surgical subtypes: local tumor destruction/excision, partial excision, radical excision with limb salvage, limb amputation, and major amputation. Univariate analysis was performed assessing patient survival length for each surgical subtype. Data was analyzed using SPSS and statistical significance was set at α = 0.05. Results: A total of 3827 patients were analyzed. Patients who received surgery survived significantly longer than those who did not (p &lt; .00001). Patients who underwent major amputations had shorter median survival times ranging from 24-74 months. Patients who received radical tumor excision with limb salvage had the longest survival of any surgical subtype with a mean of 130.1 months and survived significantly longer than patients receiving local tumor resection, partial resection, partial and total limb amputations, or any major amputation (p &lt; .001). Patients with local tumor destruction survived similarly to those with local tumor excision (p &gt; .05). Patients with partial or total limb amputation had significantly better survival than patients with major limb amputation (p &lt; .01). Conclusions: We found numerous significant differences between the different surgical subtypes used to treat patients with OSC. Radical excision with limb salvage proved to yield the best survival outcomes, with significantly higher survival when compared to almost all other surgical subtypes (excluding local tumor destruction). Future studies should investigate additional parameters within each surgical subtype to assess the impact that variables like patient demographics and socioeconomic status, tumor characteristics, and surgical center may have on access to care and survival outcomes.[Table: see text]
HGG-20. PRMT5 promotes the formation and growth of pediatric high-grade glioma by maintaining tumor stem cell populations
Authors: John DeSisto, Aaron Knox, Ilango Balakrishnan, Hannah Chatwin, Philip Coleman, Sujatha Venkataraman, Rajeev Vibhakar, Adam Green
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Pediatric high-grade gliomas (PHGG) are aggressive, undifferentiated CNS tumors comprising two broad subtypes: diffuse midline glioma with H3K27M mutations (DMG) and cortical high-grade glioma (H3K27-wild-type (wt) PHGG). During normal development, PRMT5 promotes stem cell self-renewal through methylation of arginine residues in histone tails. We hypothesized that PRMT5 controls self-renewal essential to the proliferation of PHGG tumor initiating cells (TICs). METHODS: We identified PRMT5 as potentially oncogenic in PHGG through a screen of 4,139 shRNAs targeting 406 genes with epigenetic activity. To elucidate PRMT5’s activity, we used lentiviral shRNA delivery to knock down (KD) PRMT5 expression in four DMG and one H3K27-wt PHGG cell lines. We performed in vitro growth, cell cycle, apoptosis, limiting dilution and bulk RNA-Seq assays to determine the phenotypic effects of PRMT5 KD. To identify PRMT5’s gene targets, we performed cleavage under targets &amp; release using nuclease (CUT&amp;RUN) followed by qPCR and are currently performing CUT&amp;RUN-Seq. We orthotopically implanted PRMT5 KD PHGG cells into mice and tracked survival, tumor growth and tumor histological characteristics. RESULTS: In vitro, PRMT5 KD reduced cell growth (p&amp;lt;0.001), slowed cell cycle progression and increased apoptosis. PRMT KD also slowed neurosphere formation, demonstrating reduced self-renewal (p&amp;lt;7E-9). Geneset expression analysis showed PRMT5 KD reduced expression of self-renewal genes and increased expression of differentiation genes (FDR&amp;lt;0.0001). In vivo, PRMT5 KD reduced tumor growth, as monitored by bioluminescence and MRI, and aggressiveness, based on Ki-67 staining (p&amp;lt;0.05), leading to increased survival (p&amp;lt;0.001). CUT&amp;RUN-qPCR results showed PRMT5 KD led to decreased expression and H3K4me3 promoter occupancy at PAX3, and decreased expression and increased H3K27me3 occupancy at S100A6. PAX3 and S100A6 are oncogenes that preserve TIC self-renewal. CONCLUSION. In vitro experiments show that PRMT5 KD epigenetically reduces TIC self-renewal. In vitro and in vivo, PRMT5 KD reduced PHGG tumor cell growth and aggressiveness.
PATH-04. Array-based global DNA Methylation profiling of mouse brain tumors allows comparison to human tumors
Authors: Melanie Schoof, Michael Spohn, Mario Dorostkar, Sina Neyazi, Michael Bockmayr, Fredrik Swartling, Daisuke Kawauchi, Richard Gilbertson, Jessica Taylor, Yanxin Pei, Rainer Glass, Jiying Cheng, Natalia Moreno Galarza, Juergen Hench, Jochen Herms, Philipp Jurmeister, Leonille Schweizer, David Capper, Patrick Harter, Christian Thomas, Martin Hasselblatt, Mirjam Blattner-Johnson, David Jones, Stephan Frank, Kornelius Kerl, Ulrich Schüller
Journal: Neuro-Oncology (2022)

Abstract The classification of human brain tumors by global DNA methylation profiling has become an essential part of modern integrated neuropathological diagnostics. It has proven to reliably identify known and novel brain tumor (sub-)types that are biologically and clinically distinct. Therefore, this technique has critically improved diagnostic accuracy and risk stratification of brain tumor patients. Although indispensable for the understanding of tumor biology and for preclinical drug trials, the comparison of genetically engineered mouse models to human brain tumors is still difficult. The assessment of tumor morphology only provides an approximate picture, and transcriptomic data from human brain tumors are sparse and suffer from platform-related technical incomparability. Here, we show array-based DNA methylation profiling of well-established murine brain tumors, such as Wnt and Shh medulloblastoma, YAP and RELA ependymoma, ETMR, and AT/RT. Similar to human brain tumors, unbiased clustering methods revealed distinct methylation profiles and mean methylation levels for mouse brain tumors types. Analyses were possible for fresh-frozen as well as for paraffin-embedded tissue, and copy number alterations could be inferred from methylation profiles. Most importantly, first results suggest that inter-species comparisons allow the classification of brain tumors from known or novel mouse models based on the constantly growing spectrum of human brain tumor types and subtypes with hundreds of thousands of available datasets. As an example, upon DNA methylation profiling, cerebellar tumors arising in Math1-cre::SmoM2Fl/+ mice display the highest similarity to human SHH medulloblastoma when compared to multiple human brain tumor entities including WNT and Non-WNT/Non-SHH medulloblastoma. These results suggest that global DNA methylation profiling may add another very important level of information to the characterization of genetically engineered mouse models.
Post-radiation cisplatin and etoposide as systemic treatment in newly diagnosed adult medulloblastomas: A retrospective, single institution, longitudinal evaluation of clinical outcomes and toxicity.
Authors: Edina Komlodi-Pasztor, Matthias Holdhoff, Byram Hirsch Ozer, Vasu Munjapara
Journal: Journal of Clinical Oncology (2022)

e14046 Background: Medulloblastomas are malignancies of the posterior fossa with metastatic potential to the central nervous system. While a common pediatric malignancy, they are rare in adults. Extrapolating treatment regimens from pediatrics to adults is fraught as adults can developmentally tolerate higher radiation doses, but have less bone marrow reserve and therefore risk higher myelosuppressive toxicities with adjuvant systemic therapy. A standard systemic regimen for adults has not been delineated, though craniospinal radiation alone is likely insufficient in most cases. In the absence of well-established guidelines, our institution has historically used a combination of cisplatin (60 mg/m2 on Day 1) and etoposide (60-120 mg/m2 on Days 1-3 or 1-5) repeated in three-week cycles for three to a maximum of six cycles, but the literature to support this regimen is scant. Methods: In this retrospective chart evaluation, we reviewed the medical information of patients who were seen for newly diagnosed adult medulloblastoma between 1995 and 2020 at Johns Hopkins Hospitals. Those who met our pre-specified criteria (adjuvant treatment with etoposide/cisplatin within six months of craniospinal irradiation, sufficient data on toxicity before and after radiation, during chemotherapy, and one month after completion of the regimen, as well as sufficient clinical follow-up) were included in the analysis. Hematological toxicities were graded by NCI CTCAE guidelines. Follow-up for progression and survival were calculated from the end of the last chemotherapy administration and plotted on swimmers plots. Results: Ten out of 74 total adult medulloblastoma patients had adequate data about the tolerability of the regimen and clinical follow-up. Median time to follow-up was 46 months (range 4.5-164 months). Eight patients experienced Grade 3 and 4 hematological toxicities. Seven patients completed their planned treatment course, while two patients discontinued treatment prematurely because of hematological toxicities and one due to ototoxicity and fatigue. Three out of the ten patients progressed post-chemotherapy at 1 month, 24.5 months, and 44 months. Both early-progression patients died (7 and 29.5 months respectively), while the remaining eight are alive without evidence of progression. Conclusions: The data suggest a combination regimen of cisplatin and etoposide after craniospinal radiation in newly diagnosed adult medulloblastoma patients has acceptable toxicity and survival outcomes in this small patient cohort and compare favorably to other limited datasets in the literature. Further study is warranted to validate this as a recommended regimen.
Oncological and safety profiles in patients undergoing simultaneous transurethral resection of bladder tumor and prostate: Results from a large multicenter international collaboration
Authors: E. Laukhtina, M. Moschini, W. Krajewski, J.Y. Teoh, G. Ploussard, F. Soria, F. Roghmann, M.A. Muenker, M. Roumiguie, M. Alvarez-Maestro, V. Misrai, A. Antonelli, A. Tafuri, G. Simone, R. Mastroianni, H. Zhao, R-G. Rahota, S. Scuderi, V. Petov, D. D`andrea, K. Mori, F. Montorsi, D. Enikeev, S.F. Shariat, B. Pradere
Journal: European Urology (2022)
DIPG-04. Feasibility and early results of phase 2 open label randomized study of radiotherapy(RT), concomitant nimotuzumab and vinorelbine and re-irradiation at relapse, versus multiple elective radiotherapy courses with concomitant vinorelbine and nimotuzumab for newly diagnosed childhood and adolescence Diffuse intrinsic Pontine Glioma (DIPG)
Authors: Maura Massimino, veronica Biassoni, Angela Mastronuzzi, Elisabetta Schiavello, Francesco Barretta, Lucia Quaglietta, Claudia Milanaccio, Emilia Pecori, Antonella Cacchione, Luna Boschetti, Valentina Di Ruscio, Silvia Chiesa, Giuseppe Scimone, Salvina Barra, Lucia De Martino, Antonia Ramaglia, Stefania Picariello, Antonio Verrico, Ombretta Alessandro, Sabina Vennarini, Marta Podda, Giovanna Gattuso, Giuseppe Cinalli, Manila Antonelli, Piergiorgio Modena, Loris De Cecco, Francesca R Buttarelli, Lorenza Gandola
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: The purposes of this trial were to evaluate the feasibility, response, PFS/OS of a randomized study comparing two different RT schedules for DIPG while administering the same systemic treatment. METHODS: Patients: 2-21 years-old with a not-pretreated radiologically verified DIPG (MRI blindly reviewed at diagnosis and every 12 weeks thereafter) and symptoms duration below 6 months. Biopsy was required if suggested by atypical imaging. Vinorelbine 20 mg/m2+nimotuzumab 150 mg/m2 were administered weekly for 12 weeks; thereafter every other week until tumor progression or for up to 2 years. Standard(ST) arm included focal RT at total dose of 54Gy (1.8Gy/day); for local progression re-irradiation was proposed at 19.8Gy, in case of dissemination craniospinal irradiation(CSI) at 36Gy was adopted. Experimental(SP) arm included three elective courses of RT at defined timepoints at 36Gy, 19.8Gy and 19.8Gy with possible reirradiation for relapse at 9 Gy. Incidences of local(L) and distant(D) progression were assessed in a competing risk setting. RESULTS: Aggregated preliminary results are given for 4 Italian centers. 54 pts were screened and 51 included, 27 in ST, 28 males, median age 7 years (range 3-17). Median time of observation was 17.9 months. Twelve patients needed a shunt, 10 during treatment; 20 were biopsied, in 18 cases according local protocols. 19/20 tumors had H3.3 K27 mutation. 41 relapsed, 28 locally, 13 with a component of dissemination. 36 died, one for tracheotomy bleeding. SP irradiation was feasible and never produced significant radionecrosis. Median EFS/OS were 7.3/12.9 months, respectively; EFS/OS at 1 year were 19.0%/57.3%, not differing between patients with local vs. disseminated relapses. Patients submitted to biopsies had more dissemination (P=0.04) and less local progression (P=0.077). CONCLUSIONS: Treatment was feasible and OS confirmed previous results obtained in a single center. Randomization results will be later reported.
Oral minoxidil for the treatment of late alopecia in cancer survivors.
Authors: Alyce Mei-Shiuan Kuo, Rachel E. Reingold, Kwami Ketosugbo, Alexander Pan, Stephen W Dusza, Lukas Kraehenbuehl, Devika Gajria, Diana E Lake, Jacqueline Bromberg, Shari Beth Goldfarb, Tiffany A. Traina, Monica N. Fornier, Ayca Gucalp, Megan Dauscher, Alina Markova, Mario E. Lacouture
Journal: Journal of Clinical Oncology (2022)

12022 Background: Late alopecia is defined as incomplete hair regrowth &gt; 6 months following cytotoxic chemotherapy or from initiation of endocrine therapy. It has been reported in up to 25-30% of cancer survivors and is associated with decreased quality of life and reduced dose intensity of cancer therapies. Minoxidil is an aminopyridine potassium channel opener, resulting in vasodilation and premature entry of resting hair follicles into the anagen (growth) phase and increase in hair follicle size. This study aims to assess clinical outcomes and adverse events of oral minoxidil for the treatment of cancer therapy-related late alopecia. Methods: We retrospectively assessed all women with late alopecia treated with oral minoxidil (1.25 mg daily) evaluated at an oncodermatology referral program between 1/2018-5/2021. Outcomes were assessed by standardized photography (4 views) and trichoscopy (HairMetrix, Canfield Scientific, Inc.). Trichoscopy recorded hair density (hair count/cm 2 ) and hair thickness (shaft diameter) at uniform frontal and occipital target areas (12 and 36 cm midline from the glabella, respectively). Adverse events were recorded and graded using CTCAE v5.0. Descriptive statistics were used to summarize the patient demographics and clinical characteristics. Changes in trichoscopy measurements from baseline to follow-up were estimated using paired t-tests. Results: Two hundred and sixteen patients (mean age 57.8±13.7) were included for analysis. Thirty-one (14%) received chemotherapy alone, 65 (30%) endocrine monotherapy, and 120 (56%) chemotherapy followed by endocrine therapy. The majority of patients (n = 170, 79.1%) had a history of breast cancer. Standardized photography assessments (n = 119) after a median of 105 days (IQR = 70) on oral minoxidil revealed clinical improvement in 88 (74%). Trichoscopy assessments (n = 42) after a median of 91 days (IQR = 126) demonstrated increased frontal hair density (124.2 vs 153.2 hairs/cm 2 , p = 0.008) and occipital hair density (100.3 vs 123.5 hairs/cm 2 , p = 0.004). There was no statistically significant difference in average frontal or occipital hair thickness (69.3 vs 67.3 μm, p = 0.22, and 70.3 vs 69.9 μm, p = 0.84, respectively). No patients reported discontinuation of oral minoxidil due to adverse effects. Conclusions: Oral minoxidil may benefit both frontal and occipital late alopecia in cancer survivors treated with cytotoxic and/or endocrine therapy. This regimen was well tolerated by patients. Prospective, controlled studies are needed to confirm these observations.
Disparity between Ki67 measurements and tumor gene expression tests in patients with hormone-sensitive early breast cancer from the OPTIMA preliminary trial.
Authors: Robert C. Stein, Andrea Marshall, Jane Bayani, Andreas Makris, Iain R. MacPherson, Luke Hughes-Davies, Monika Sobol, Tammy Piper, Georgina Dotchin, Helen Higgins, Abeer Shaaban, Sarah E. Pinder, Janet Dunn, John Bartlett
Journal: Journal of Clinical Oncology (2022)

567 Background: Tumor gene expression tests are increasingly used in breast cancer management. The Ki67 biomarker has been proposed as an inexpensive alternative for making chemotherapy decisions, has demonstrated utility for determination of endocrine therapy responsiveness and is included in the FDA license for adjuvant abemaciclib. We have compared Ki67 measurements with tumor gene expression test results for patients included in the OPTIMA prelim trial. Methods: We compared Ki67 %staining with the results of Oncotype DX, Prosigna and MammaPrint performed by the test vendor. Ki67 was determined in a single laboratory on triplicate tissue micro-arrays using quantitative image analysis including a 10% manual quality control check. We used kappa statistics to measure agreement between tests, divided into groups using the pre-defined test score boundaries for high vs. not high risk. Results: Data were available for 259 patients. Using ≥20% staining to define a high Ki67 score, kappa values (95% CI) for agreement with Prosigna were: 0.39 (0.28-0.49); Oncotype DX: 0.27 (0.18-0.36); and MammaPrint: 0.38 (0.27-0.49). Kappa values &lt;0.2 are conventionally interpreted as showing slight agreement and 0.21-0.4 as fair agreement. A detailed breakdown of the comparisons of Ki67 with Prosigna and Oncotype DX is tabulated. Conclusions: Agreement between Ki67 and tumor gene expression tests is limited. Therefore, Ki67 values cannot accurately be used to reflect any of the molecular scores assessed here, all of which are well validated prognostic biomarkers. The use of Ki67 to determine suitability for adjuvant chemotherapy requires validation before it can replace the existing tests. Tumor gene expression tests may prove superior to Ki67 for the identification of patients likely to benefit from adjuvant abemaciclib. OPTIMA prelim is registered as ISRCTN42400492 and funded by the UK NIHR Health Technology Assessment Programme, award number 10/34/01. Clinical trial information: ISRCTN42400492. [Table: see text]
DIPG-17. CD155 regulates cell growth and immune evasion in diffuse intrinsic pontine glioma
Authors: Theophilos Tzaridis, Tanja Eisemann, Augusto F Andrade, Jennifer L Hope, Megan M Romero, Oren J Becher, Nada Jabado, Linda M Bradley, Robert J Wechsler-Reya
Journal: Neuro-Oncology (2022)

Abstract There is an unmet need for more effective treatment strategies for diffuse intrinsic pontine glioma (DIPG), a devastating brain tumour arising in children and young adults. While immunotherapy is emerging as a powerful approach to treatment of other cancers, clinical trials with immune checkpoint inhibitors have failed to show a survival benefit for DIPG patients. In this study, we analysed the expression of immune checkpoint molecules on the surface of human and murine DIPG cells by flow cytometry and identified CD155 and B7-H3 as the most highly expressed checkpoint molecules, with minimal expression of PD-L1, PD-L2, Galectin-9, CEACAM-1, CD86, CD252 and CD137. These findings were confirmed in primary patient samples from pediatric brain tumours, including high-grade gliomas, medulloblastomas and ependymomas. To test whether CD155 inhibition increases susceptibility to CD8+ T cell killing in vitro, we cultured DIPG cells expressing ovalbumin (OVA) with CD8+ T cells from OT-I mice, which express T cell receptors specific for OVA. Addition of CD155 blocking antibodies to these cultures increased expression of T cell activation markers (CD25, CD44 and CD69) as well as T cell-mediated tumour killing, supporting the notion that CD155 can function as an immune checkpoint in DIPG. In addition to its effects on T cells, CD155 also exerted direct effects on tumour cells: treatment with anti-CD155 antibodies led to impaired cell viability, and shRNA-mediated knockdown of CD155 resulted in reduced cell proliferation in vitro. Strikingly, knockdown of CD155 also led to reduced growth of DIPG cells in vivo, and mice transplanted with the CD155-deficient cells had a clear survival benefit compared to mice transplanted with wild type cells. These studies demonstrate that CD155 functions as an immune checkpoint and as a regulator of tumor growth in DIPG, and suggest that targeting CD155 could be a valuable therapeutic strategy for this devastating disease.
Rapid adoption of immunotherapy in community health systems, associated with changing treatment guidelines.
Authors: Alissa Winzeler-Cotton, Akila Subramanian, Kaitlyn Kane, Chenan Zhang, Matthew J. Rioth, Anna B. Berry, Thomas D. Brown
Journal: Journal of Clinical Oncology (2022)

e18610 Background: In the quickly evolving landscape of developmental therapeutics, uptake of new standards of care is a critical issue. Community health systems (CHS) provide &gt; 50% of cancer care in the US. Rapidly changing immunotherapy (IO) guidelines provide a window into changing practice patterns. This analysis describes how IO use has evolved within CHS. Methods: Patients (pts) selected were ≥ 18 years, diagnosed with advanced or metastatic NSCLC 2015-2020, with 2+ EHR encounters before 4/1/2021. Two sub cohorts were analyzed. Cohort 1: pts receiving IO in any line of therapy (L); first use of IO by L was assessed over time. Cohort 2: pts receiving any first L (1L) therapy; 1L use of IO, alone or with chemotherapy (IO combo), was assessed over time. Results: In cohort 1, IO use in 1L grew from 24% of all IO pts in 2016 to 93% in 2020, increasing from 33% in Q4 2016 to 62% in Q1 2017. In cohort 2, 1L therapy shifted from 4% of all pts receiving IO in 1L in 2016 to 59% in 2020, increasing from 6% in Q4 2016 to 24% in Q1 2017. Within IO 1L pts, IO combo use grew from 29% to 68% in 2020, increasing from 35% in Q1 2018 to 53% in Q2 2018. Conclusions: We observed two rapid shifts in care patterns. First, 1L IO use grew rapidly from Q4 2016 to Q1 2017, following 1L IO approval (10/2016). Second, 1L IO use shifted rapidly toward IO combo use from Q1 2018 to Q2 2018, coinciding with pivotal trial results and FDA priority review (4/2018), but preceding label expansion (8/2018). Two RWD analyses from independent oncology practices observed less substantial shifts during similar periods of time. These results demonstrate that CHS can rapidly adjust to evolving clinical evidence and associated changes in standards of care.[Table: see text]
Risks and benefits of partial nephrectomy with limited or without ischemia time
Authors: A. Larcher, D. Cignoli, G. Fallara, G. Rosiello, G. Basile, G. Colandrea, G. Baiamonte, F. Cei, G. Musso, D. Canibus, R. Bertini, P. Karakiewicz, A. Mottrie, F. Dehó, A. Gallina, F. Montorsi, A. Salonia, U. Capitanio
Journal: European Urology (2022)